to insulin; this explains, in part, the reductions in fasting and postprandial free fatty acid, LDL, and TG concentrations and the increase in plasma HDL levels in adults who adhere to a rigorous diet-and-exercise regimen. The effect of exercise on plasma TG is mediated through induction of lipoprotein lipase and reduction in TG production.

Exercise increases hepatic glucose uptake and glycogen synthesis and decreases hepatic glucose production, thereby reducing fasting glucose and insulin concentrations. In skeletal muscle, exercise stimulates insulin-dependent glucose uptake and thereby reduces postprandial glucose levels; this action is mediated by increases in muscle GLUT-4 synthesis and induction of GLUT-4 translocation from intracellular pools to the plasma membrane [43]. The induction of GLUT-4 activity may be mediated, in turn, by an increase in cellular levels of adenosine monophosphate (AMP)-activated protein kinase (AMPK) [44]. Activation of AMPK after an acute bout of exercise promotes increased cycling of existing GLUT-4 transporters in skeletal muscle, as well as enhanced expression of hexokinase II and mitochondrial enzymes.

Several studies suggest that insulin action is related to the oxidative capacity of skeletal muscle. Insulin-resistant individuals (including those with type 2 diabetes) have reduced activities of muscle-oxidative enzymes; aerobic-exercise training increases muscle-oxidative enzyme activity and improves insulin sensitivity by 26 percent to 46 percent. The effect of exercise on oxidative-enzyme activity may reflect, in part, an increase in mitochondrial size [45]. Interestingly, weight loss alone may improve insulin sensitivity, but may not alter fasting rates of lipid oxidation. In contrast, weight loss coupled with exercise increases fat oxidation.

COMPLICATIONS OF TYPE 2 DIABETES

Presenting Manifestations and Acute Complications

As noted previously, children with type 2 diabetes may be asymptomatic when first identified. On the other hand, many have longstanding polyuria and polydipsia, and some have lost weight prior to diagnosis. Presenting manifestations may include vaginal candidiasis, superficial bacterial and urinary-tract infections, cervical adenitis, or Bartholin gland abscess. Mild ketoacidosis occurs in 30 percent to 40 percent of African American and Hispanic American children with type 2 diabetes; less commonly, the child presents with nonketotic hyperosmolarity associated with severe hyperglycemia.

Obese diabetic children commonly develop fatty liver, which may progress to cirrhosis. Other complications in obese children may include cholecystits, pancreatitis, and pseudotumor cerebri. Many patients have a history of asthma or sleep apnea, which results from upper-airway obstruction (possibly from fat deposition in pharyngeal tissues) and decreased residual lung volume (caused by increased intraabdominal pressure). Menstrual irregularity and mild hirsutism are common in adolescent girls, many of whom may have PCOS. Microalbuminuria may be detected within a short time after diagnosis, particularly in obese, hypertensive adolescents. Some patients have a form of focal glomerulosclerosis.

The development of insulin resistance and type 2 diabetes have ominous implications for long-term cardiovascular health. Microvascular complications, including neuropathy, retinopathy, and microalbuminuria, all occur with increased frequency in adults with IGT as well as diabetes, and rates of myocardial infarction and stroke are increased twofold to fivefold [46-49].

Obesity, insulin resistance, and type 2 diabetes in childhood predispose to vascular complications in later life. Severe obesity in 9- to 11-year-old children is associated with increased stiffness of the carotid arteries, and obesity in adolescence predisposes to increased carotid intima-media thickness (CIMT) in young adulthood. Weight loss after adolescence may reduce adult CIMT [50]. Even normotensive young people (age 9-12 years) with less-severe obesity (BMI 25±3) may show evidence of brachial-artery endothelial dysfunction and increased CIMT [51]. Among 93 subjects in the Bogalusa Heart Study who underwent autopsy at age 2-39 years, the prevalence of fatty streaks and fibrous plaques in the aorta and coronary arteries increased with age and correlated positively with standard deviation (z) scores for BMI, serum TGs, cholesterol, and blood pressure [52]. The combination of multiple risk factors increased exponentially the extent of arterial intimal surface involvement. Postmortem analysis of more than 3000 subjects who died of natural causes at 15-34 years of age [53] showed that obesity and impaired glucose tolerance were associated with progression of atheromatous lesions in adolescents and young adults. In young men, BMI and abdominal-fat mass correlated with the number and size of fatty streaks and raised lesions in the right and left anterior descending coronary arteries. In both women and men, the extent of fatty streaks correlated with glycohemoglobin concentrations. Severe glucose intolerance likely accelerates the progression of vascular disease; a Canadian study [54] of 52 young adults (age 18-33 years) who developed type 2 diabetes before age 17 showed one with a toe amputation (1.9 percent) and five on dialysis (9.6 percent); two of the latter had died (3.8 percent), and one was blind (1.9 percent).

Hyperglycemia Dyslipidemia

Insulin resistance Hyperinsulinemia

NOS inhibition PARP activation ^ Cytokines

Growth factors Prothrombotic factors

Na, water reabsorption SNS activation

Hypertension

Endothelial dysfunction

Vasoconstriction M-

Vascular insufficiency Atherogenesis

The pathogenesis of vascular disease involves a complex web of hormones, growth factors, vasoactive agents, cytokines, oxygen radicals, and cellular-adhesion molecules (Figure 11.3) [46, 55, 56]. Under normal conditions, insulin stimulates vasodilatation through induction of nitric oxide synthase (NOS) and generation of NO in vascular endothelial cells. In obesity and other states associated with insulin resistance, the production of NO is disrupted, leading to vasoconstriction and tissue ischemia. Hyperglycemia contributes to endothelial dysfunction and vascular insufficiency through production of superoxide radicals; reactive-oxygen species cause direct endothelial damage and deplete endothelial NO, reducing vascular reactivity. Oxygen radicals also activate poly(ADP ribose) polymerase (PARP), which inhibits glyceraldehyde phosphate dehydrogenase activity and thereby promotes the formation of polyols, glucosamine, and advanced glycation end products and the activation of protein kinase C [57]. These end products promote the development of microvascular and macrovascular disease. Glucose-dependent expression of growth factors (such as VEGF, EGF, and IGF-1) and cytokines (IL-1, IL-6, and TNF alpha) and a reduction in plasma adiponectin concentrations aggravate these effects by stimulating migration and proliferation of smooth-muscle cells and increasing leukocyte adhesion to endothelial surfaces. Reduction in NO availability enhances platelet aggregation and limits fibrinolysis, promoting the progression of atheromatous clots. Increases in the concentrations of the prothrombotic plasminogen activator-1, which is also overexpressed by adipose tissue in obesity, may contribute to fibrin deposition on luminal walls, and production of endothelin-1 in terminal blood vessels is increased, promoting vasoconstriction [56]. These effects are exacerbated by dyslipidemia and hypertension; increases in blood pressure may reflect insulin-dependent increases in sodium, and water reabsorption and activation of the sympathetic nervous system [58]. Reductions in tissue perfusion limit insulin-mediated glucose disposal and may increase circulating glucose concentrations, creating a vicious cycle.

PREVENTION OF TYPE 2 DIABETES IN HIGH-RISK SUBJECTS

Lifestyle Intervention

The first objective in preventing type 2 diabetes is to assess in detail the family history. Particular attention should be focused on those with first- or second-degree family members with type 2 diabetes, hypertension, or early onset cardiovascular disease or stroke. In such cases, early intervention to prevent metabolic complications is essential. Given the risks of adult type 2 diabetes and cardiovascular disease among infants born to diabetic mothers and children born SGA, it is best for a prospective mother to be healthy and lean even before she gets pregnant and to remain healthy and well-nourished during pregnancy. If at all possible, her newborn baby should be breast-fed.

The older child should be introduced to healthy meals containing lean meats, chicken and fish, low-fat dairy products, whole grains, green, leafy vegetables, and nuts. Sugary drinks, such as soda, juice, or sweet tea, should be discarded in favor of milk and water, and the intake of fried foods, white bread, pasta, gravy, potatoes, and rice should be limited.

In obese subjects, moderate reductions in body-fat mass can reduce the risks of type 2 diabetes and cardiovascular complications if weight loss is accompanied by negative energy balance. Mild caloric restriction is safe for obese children and can be effective when families are motivated and encouraged to change longstanding feeding behaviors. Significant reductions in weight are unusual and often transient unless caloric restriction is accompanied by increased energy expenditure. Nevertheless, even relatively small reductions (5 percent to 10 percent) in BMI z score may increase insulin sensitivity, enhance glucose tolerance, improve measures of cardiovascular health, and reduce the risk of progression to type 2 diabetes [59]. Diets severely restricted in calories produce more dramatic weight loss but cannot be sustained under free-living conditions. Very low-calorie, low-protein diets are potentially dangerous and may precipitate recurrent and futile cycles of dieting and binge eating.

The child should be encouraged to remain active, and prolonged sedentary activities (television, computer games) should be discouraged. Family and communal pursuits, such as walking, hiking, bike riding, and ball play, are best for young people. The exercise should be fun and participatory. More intensive and directed exercise may be useful in the setting of obesity. A randomized, modified crossover study [60] of 79 obese children (age 7-11 years) demonstrated that four months of exercise training (40 minutes of activity five days a week) decreased fasting insulin (10 percent) and TG concentrations (17 percent) and reduced percent body fat (5 percent) even in the absence of dietary intervention. The effects on plasma insulin and body fat were reversed when training was discontinued. An eight-week trial of cycle ergometry and resistance training in obese adolescents reduced abdominal (7 percent) and trunk (3.7 percent) fat mass and normalized flow-mediated dilation of the brachial artery [61]. Exercise exerts beneficial effects on general cardiovascular health and, in combination of a low-saturated-fat diet, may reverse hepatic steatosis.

The capacity for voluntary exercise declines as BMI rises. It is therefore critical to begin regular exercise before the child becomes morbidly obese and functionally immobile.

Benefits from lifestyle intervention are most likely to be reaped when diet-and-exercise programs are coordinated with individual and family counseling and behavior modification. School-based programs, supported by community groups and by state and federal agencies, may assist families and reduce the child's sense of isolation, frustration, and guilt.

B. Pharmacotherapy in Diabetes Prevention

Unfortunately, the long-term success of lifestyle intervention has been disappointing; rates of obesity and insulin resistance in children and adults continue to increase despite widespread recognition of the dangers of dietary indiscretion and a sedentary existence. This may reflect, in part, the resistance of complex feeding and activity behaviors to change, as well as the power of social and economic forces that shape lifestyles in the modern, industrialized world. Metabolic and hormonal adaptations to initial weight loss may also create barriers to long-term success; for example, reductions in food intake and body weight decrease the circulating concentrations of tri-iodothyronine (T3) and leptin and increase circulating concentrations of ghre-lin. The fall in T3 and leptin levels limits energy expenditure and sympathetic nervous-system activity, and may facilitate rebound food intake. Hunger may be intensified by the rise in plasma ghrelin, which stimulates food intake [62]. Food restriction also causes a secondary resistance to growth hormone (GH) action and an increase in insulin sensitivity that may reduce the rates of lipolysis and fat breakdown [63, 64].

The obstacles to success with lifestyle intervention have stimulated interest in pharmacologic approaches to diabetes prevention in obese children. Studies of phar-macoprevention have focused on drugs that limit nutrient absorption and on agents that reduce insulin production through enhanced insulin action. Only a few investigations have been performed in children, though initial findings are consistent with those in adults.

1. Drugs that Limit Nutrient Absorption

Orlistat inhibits pancreatic lipase and thereby increases fecal losses of TG. Orlistat reduces body weight and total and LDL cholesterol levels, and reduces the risk of type 2 diabetes in adults with impaired glucose tolerance. In obese adolescents, the combination of orlistat with lifestyle intervention reduced weight (-4.4 ± 4.6 kg), BMI, total-cholesterol, LDL, fasting-insulin, and fasting-glucose concentrations, and increased insulin sensitivity during a three-month trial period [65]. There was considerable variability in response to the drug. Variable reductions in body weight (-12.7 to +2.5 kg) and fat mass were also noted in a study of 11 morbidly obese children age 7-12 years. Side effects are tolerable as long as subjects reduce fat intake, but vitamin A, D, and E levels may decline despite multivitamin supplementation. High study-dropout rates (25 percent or more) suggest that long-term fat restriction is problematic in teenagers; dietary noncompliance results in flatulence and diarrhea that ultimately prove unacceptable.

Acarbose, an alpha glucosidase inhibitor, may reduce progression to type 2 diabetes by limiting gastrointestinal absorption of carbohydrate. The STOP-NIDDM trial [66] demonstrated a 25 percent to 36 percent reduction in type 2 diabetes in obese adults (mean age 55 years, mean BMI 31) with impaired glucose tolerance. Postprandial glucose and insulin concentrations were reduced and weight declined slightly in patients treated with acarbose (100 mg tid) for a mean of 3.3 years. In addition, the rate of development of cardiovascular events (coronary heart disease, cardiovascular death, congestive heart failure, stroke, and peripheral vascular disease) was only one-half that in the placebo group. However, the drop-out rate in the acarbose group was 24 percent, and the gastrointestinal side effects of the medication, which include flatulence and diarrhea, limit its acceptability in children and adolescents.

2. Insulin Suppressors and Sensitizers

The synthesis and storage of TG in adipose tissue is stimulated by insulin. Thus, increases in nutrient-dependent insulin production and fasting hyperinsulinemia may contribute to fat storage and limit fat mobilization. By reducing fasting or postprandial insulin concentrations, certain pharmacologic agents may prove beneficial in the treatment of obese children and adults.

a. Metformin

Metformin is a bisubstituted, short-chain hydrophilic guanidine derivative that works through activation of AMP protein kinase [67]. Its major site of action is the liver: The drug increases hepatic glucose uptake, decreases gluconeogenesis, and reduces hepatic glucose production (Figure 11.4) [68, 69]. Metformin increases

insulin-receptor binding, but has variable and often only minor effects on peripheral insulin sensitivity; there is no effect on skeletal-muscle glucose uptake or plasma-adiponectin concentrations [68, 69]. Major benefits of the drug include decreased food intake, weight loss, decreased fat stores (subcutaneous > visceral), and improved lipid profiles. The drug also reduces liver enzymes in patients with hepatic steatosis [70]. Of even greater importance, long-term studies suggest that metformin reduces cardiovascular morbidity and mortality in diabetic adults [71].

In obese adults with normal glucose tolerance, and in obese women with PCOS, treatment with metformin reduced daily food intake, body weight, body fat, and plasma-leptin concentrations, and downward trends were noted in LDL and total plasma cholesterol [72-74]. In normal-weight (BMI < 25), postmenarchal, young (13.6-22 years old) women with ovarian hyperandrogenism, hyperinsulinemia, and normal glucose tolerance, metformin increased insulin sensitivity and reduced plasma insulin, TG, and testosterone levels and the ratio of LDL to HDL. The addition of flutamide, an androgen antagonist, potentiated the effects of metformin on TG, LDL/HDL, and adrenal-androgen concentrations and markedly reduced hirsutism scores. The combination of metformin and flutamide reduced abdominal and total body-fat mass and increased lean body mass despite reductions in plasma GH and IGF-1 levels [75-77].

There have been two randomized, double-blind, placebo-controlled studies of metformin in obese adolescents with insulin resistance, normal glucose tolerance, and a positive family history of type 2 diabetes. In the first trial (n = 29), metformin reduced BMI Z score (3.6 percent relative to placebo controls), plasma leptin, and fasting glucose (-9.8 mg%) and insulin (-12 uU/ml), even in the absence of dietary intervention [78]. Since increases in BMI and fasting glucose and insulin concentrations predict the development of type 2 diabetes in target populations [79], these findings suggested that metformin might prove useful in preventing glucose intolerance in high-risk adolescents.

In the second trial (n = 24), the combination of a low-calorie diet (1500-1800 kcal/day for girls and boys, respectively) and metformin reduced weight by 6.5 percent; diet alone caused a 3.8 percent weight loss [80]. Patients treated with metformin had greater decline in body fat (-6 percent versus -2.7 percent in the placebo group), a decrease in plasma leptin levels, a 50 percent decrease in plasma insulin concentrations, and increased insulin sensitivity as determined by fasting and two-hour glucose and insulin levels. Plasma cholesterol and TG levels also declined by 22 percent and 39 percent, respectively. These findings suggested that metformin and diet may act synergistically to limit weight gain and increase glucose tolerance in obese, insulin-resistant adolescents.

The recently completed Diabetes Prevention Program [32] established the efficacy of metformin in delaying or preventing the onset of type 2 diabetes in adults (age > 25 years) with IGT. The 3,234 subjects were randomly assigned to one of three interventions. These included: a placebo group that received standard lifestyle recommendations; a metformin-treated group (850-1700 mg/d) that received standard lifestyle recommendations; and a group that received an intensive program of lifestyle modification. A fourth, troglitazone-treated group was disbanded after the